Rapid Mechanistic Bridging of an Alzheimer's Disease Plasma Protein Staging Panel Across Brain Proteomics Cohorts

Kim, C. C.; Campbell, M. K.; Burq, M.; Potocnik, A.; Stepec, D.; Cuoco, C. M.; Bronevetsky, Y.; Zafred, D.; Leung, J. M.; Cimermancic, P.

doi:10.64898/2026.08.31.748393

bioRxiv · 10.64898/2026.08.31.748393

Rapid Mechanistic Bridging of an Alzheimer's Disease Plasma Protein Staging Panel Across Brain Proteomics Cohorts

Kim, C. C.·Campbell, M. K.·Burq, M.·Potocnik, A.·Stepec, D.·Cuoco, C. M.·Bronevetsky, Y.·Zafred, D.·Leung, J. M.·Cimermancic, P.

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Abstract

Background: Blood-based biomarkers are transforming Alzheimer's Disease (AD) diagnosis and staging. Recent multi-protein plasma panels accurately identify individuals with advanced Braak pathology, but whether these circulating biomarkers truly reflect the molecular remodeling underlying AD neuropathology remains unclear. Pre-existing datasets could answer such questions, but their reuse requires harmonized protein expression data, standardized sample annotations, and consistent study metadata. Methods: A recently reported seven-protein plasma staging panel was evaluated across multiple post-mortem proteomics brain cohorts using pre-structured datasets on the Tesorai platform. Five datasets with Braak stage data were identified and re-analyzed. A linear model was used to distinguish late (V-VI) from early Braak stage (0-IV). Because phosphorylated tau 217 (p-tau217) and amyloid beta 1-40 (A{beta}40) were not reported for any studies, raw spectra were reprocessed to quantify these proteoforms. Results: Across the cohorts, the plasma-derived biomarker panel consistently discriminated early from late disease despite heterogeneous protein coverage. Reprocessing of raw spectra recovered tau phosphopeptides absent from the original protein summaries, enabling inclusion of p-tau217, while A{beta}40 remained undetected. Together, these findings show that proteins comprising a recently proposed blood-based staging panel are associated with proteomic remodeling in the AD brain across independent cohorts. Conclusions: These findings provide biological validation for a recently proposed blood-based seven-protein staging panel by demonstrating that its constituent biomarkers are associated with disease-stage proteomic changes in AD brain tissue. More broadly, re-mining legacy mass spectrometry data for disease-relevant proteoforms, combined with pre-structured datasets, can accelerate evaluation of emerging blood-based biomarkers against neuropathological and molecular features of disease.

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Kim, C. C., Campbell, M. K., Burq, M., Potocnik, A., Stepec, D., Cuoco, C. M., Bronevetsky, Y., Zafred, D., Leung, J. M., Cimermancic, P.. 2026-09-04. Rapid Mechanistic Bridging of an Alzheimer's Disease Plasma Protein Staging Panel Across Brain Proteomics Cohorts. https://doi.org/10.64898/2026.08.31.748393

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